A stress-induced cellular aging model with postnatal neural stem cells

被引:54
作者
Dong, C-M [1 ,2 ,3 ]
Wang, X-L [1 ]
Wang, G-M [1 ]
Zhang, W-J [4 ]
Zhu, L. [1 ]
Gao, S. [1 ]
Yang, D-J [1 ]
Qin, Y. [1 ]
Liang, Q-J [2 ,5 ]
Chen, Y-L [6 ]
Deng, H-T [6 ]
Ning, K. [1 ,7 ]
Liang, A-B [4 ]
Gao, Z-L [2 ,5 ]
Xu, J. [1 ]
机构
[1] Tongji Univ, Sch Med, East Hosp, Shanghai 200120, Peoples R China
[2] Tongji Univ, Peoples Hosp 10, Shanghai 200065, Peoples R China
[3] Nantong Univ, Dept Anat & Neurobiol, Jiangsu Key Lab Neuroregenerat, Nantong, Peoples R China
[4] Tongji Univ, Dept Hematol, Tongji Hosp, Sch Med, Shanghai 200065, Peoples R China
[5] Tongji Univ, Adv Inst Translat Med, Tongji Hosp, Shanghai 200065, Peoples R China
[6] Tsinghua Univ, Sch Life Sci, Beijing 100084, Peoples R China
[7] Univ Sheffield, Dept Neurosci, Sheffield Inst Translat Neurosci SITraN, Sheffield, S Yorkshire, England
来源
CELL DEATH & DISEASE | 2014年 / 5卷
基金
中国国家自然科学基金; 国家自然科学基金国际合作与交流项目;
关键词
aging; neural stem cells; cellular senescence model; stress; DNA damage; DNA-DAMAGE RESPONSE; ADULT NEUROGENESIS; DENTATE GYRUS; SENESCENCE; REPAIR; HYDROXYUREA; CANCER; MECHANISMS; REGULATOR; STABILITY;
D O I
10.1038/cddis.2014.82
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Aging refers to the physical and functional decline of the tissues over time that often leads to age-related degenerative diseases. Accumulating evidence implicates that the senescence of neural stem cells (NSCs) is of paramount importance to the aging of central neural system (CNS). However, exploration of the underlying molecular mechanisms has been hindered by the lack of proper aging models to allow the mechanistic examination within a reasonable time window. In the present study, we have utilized a hydroxyurea (HU) treatment protocol and effectively induced postnatal subventricle NSCs to undergo cellular senescence as determined by augmented senescence-associated-beta-galactosidase (SA-beta-gal) staining, decreased proliferation and differentiation capacity, increased G0/G1 cell cycle arrest, elevated reactive oxygen species (ROS) level and diminished apoptosis. These phenotypic changes were accompanied by a significant increase in p16, p21 and p53 expression, as well as a decreased expression of key proteins in various DNA repair pathways such as xrcc2, xrcc3 and ku70. Further proteomic analysis suggests that multiple pathways are involved in the HU-induced NSC senescence, including genes related to DNA damage and repair, mitochondrial dysfunction and the increase of ROS level. Intriguingly, compensatory mechanisms may have also been initiated to interfere with apoptotic signaling pathways and to minimize the cell death by downregulating Bcl2-associated X protein (BAX) expression. Taken together, we have successfully established a cellular model that will be of broad utilities to the molecular exploration of NSC senescence and aging.
引用
收藏
页码:e1116 / e1116
页数:11
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